CD4 T cell depletion at the cervix during HIV infection is associated with accumulation of terminally differentiated T cells.

In blood, the accumulation of terminally differentiated (TD) T cells during HIV infection is associated with CD4 T cell loss and HIV disease progression. Here, we investigated the maintenance and functional characteristics of memory T cells at the cervix. We found that CD4 T cell depletion at the cervix mirrors CD4 depletion in blood. In all women, depletion of CD4 T cells at the cervix was associated with significant reductions in CD45RA- CCR7+ (central memory [CM]) T cells and the accumulation of CD45RA+ CCR7- (TD T cells). We determined whether inflammation in the genital tract was associated with the local differentiation of T cells at the cervix. In uninfected women, genital tract inflammation was associated with the accumulation of CD45RA- CCR7+ CM CD4 T cells and reduced frequencies of CD45RA+ CCR7- TD cells at the cervix. This finding may reflect the fact that, in the absence of HIV infection, TD T cells may be slowly lost in the presence of genital inflammation, while CD45RA- CCR7+ CM T cells are recruited to replenish the diminishing CD4 T cell pool. Following global stimulation with phorbol myristate acetate (PMA)-ionomycin, we noted a significant interleukin 2 (IL-2) deficit in both cervical and blood CD4 T cells from HIV-infected women compared to uninfected women, while gamma interferon (IFN-γ) production was similar, irrespective of HIV status. Few HIV-infected women had detectable IFN-γ and IL-2 HIV-specific T cell responses at the cervix, and these responses were significantly lower in magnitude than the corresponding responses in blood. These data suggest that CD4 depletion was associated with the accumulation of terminally differentiated T cell phenotypes at the cervical mucosa defective in their ability to produce IL-2. CD4 depletion and compromised immunity at the cervix may be accompanied by progressive decline of central memory-like T cells and development of T cells toward terminally differentiated phenotypes.

Homocysteine effects classical pathway of GPCR down regulation: Galpha(q/11), Galpha(12/13), G(i/o).

G protein-coupled receptors (GPCRs) are known to modulate intracellular effectors involved in cardiac function. We recently reported homocysteine (Hcy)-induced ERK-phosphorylation was suppressed by pertussis toxin (PTX), which suggested the involvement of GPCRs in initiating signal transduction. An activated GPCR undergoes down regulation via a known mechanism involving ERK, GRK2, beta-arrestin1: ERK activity increases; GRK2 activity increases; beta-arrestin1 is degraded. We hypothesized that Hcy treatment leads to GPCR activation and down regulation. Microvascular endothelial cells were treated with Hcy. Expression of phospho-ERK1 and phospho-GRK2 was determined using Western blot, standardized to ERK1, GRK2, and beta-actin. Hcy was shown to dephosphorylate GRK2, thereby enhancing the activity. The results provided further evidence that Hcy acts as an agonist to activate GPCRs, followed by their down regulation. Hcy was also shown to decrease the content of the following G proteins and other proteins: beta-arrestin1, Galpha(q/11), Galpha(12/13), G(i/o).

Weighing in on the risks and benefits of probiotic use in HIV-infected and immunocompromised populations.

Probiotics are used in the prophylaxis and treatment of several conditions, including irritable bowel syndrome, diarrhoea, necrotising enterocolitis (NEC) and colic in infants. Despite the long history of probiotic use in humans, there is still significant debate about their efficacy and safety, particularly in HIV-infected and immunocompromised individuals. Here, we reviewed the safety and adverse event (AE) reporting from clinical trials that have tested probiotics in at risk populations, including HIV-infected individuals, the terminally ill and elderly, and neonates. Our analysis suggests that the benefits of probiotic therapy outweigh their potential risks in HIV-infected populations, and in the treatment of colic and NEC in low birth weight or premature neonates. Most case reports of severe AEs were in the elderly and terminally ill, or in those with additional severe medical conditions. We conclude that probiotic use, as adjunctive treatment, is effective and safe in the majority of patients including HIV-infected individuals, although special care should be taken in individuals with extreme immunosuppression and severe medical conditions in all ages.

True burden of drowning: compiling data to meet the new definition.

The objective and aim of the study was to compile empirical data to quantify the underestimation of the true burden of drowning and to compare drowning rates using commonly reported codes compared with those revealed by use of the full range of drowning codes in ICD version 10. The authors reviewed mortality data (1999-2002) from Australia and the USA and compiled data to compare the burden of 'unintentional drowning' with that of 'all drowning'. In both Australia and the USA, drowning mortality is more than 35% higher when a full range of codes is examined. A more comprehensive representation of the drowning problem is needed to assist in strengthening prevention activities.

Seatbelt use amongst taxi drivers in Beijing, China.

Associated with explosive growth in motorization, China has the world's highest road toll with more than 100,000 deaths and 400,000 injuries annually. In response, the Chinese Government introduced the first road traffic safety law in 2003, which included mandatory use of seatbelts by drivers and front seat passengers. Noting frequent non-compliance to this seatbelt regulation by Beijing taxi drivers, the authors studied seatbelt use patterns as onboard observers in a convenience sample of 235 taxi trips. Findings indicated a low seatbelt-wearing rate among taxi drivers of 7.7%, an overt non-wearing rate of 57%, covert non-wearing of 35.3% and total non-compliance of 92.3%. As in high-income countries, adoption of proven safety strategies, including wearing safety restraints, could contribute to reducing the Chinese road toll, particularly as vehicle occupant numbers and the availability of restraints increases. Further investigation of reasons for non-compliance and pretense of wearing seatbelts is required to inform future seatbelt-wearing promotions, including attitudinal studies of taxi drivers. Seatbelt wearing rates should continue to be monitored.

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel.

The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and systemic antibody responses. Linear mixed effect modeling and partial least squares discriminant analysis was used to identify multivariate antibody signatures associated with tenofovir use. There were significantly higher response rates to gp120 Env (P=0.03), p24 (P=0.002), and p66 (P=0.009) in plasma and GT in women assigned to tenofovir than placebo gel at multiple time points post infection. Notably, p66 IgA titers in the GT and plasma were significantly higher in the tenofovir compared with the placebo arm (P<0.05). Plasma titers for 9 of the 10 HIV-IgG specificities predicted GT levels. Taken together, these data suggest that humoral immune responses are increased in blood and GT of individuals who acquire HIV infection in the presence of tenofovir gel.

Successful aortocoronary bypass in osteogenesis imperfecta.

Cardiovascular abnormalities are infrequently documented in osteogenesis imperfecta, one of a group of hereditary, generalized connective tissue disorders. A patient with osteogenesis imperfecta is described with mitral valve prolapse, significant coronary artery disease and a coronary artery aneurysm. The latter two cardiac defects are apparently rare in this disease. The option of surgery was carefully considered with regard to technical feasibility and potential deterioration of the graft anastomoses. Although successful aortocoronary bypass surgery had not been previously reported in osteogenesis imperfecta, this patient received such surgery with therapeutic benefit. Therefore, coronary artery vascularization should be considered as a safe and effective treatment modality for patients with osteogenesis imperfecta and coexisting coronary atherosclerosis.

Strategies for the prevention of cervical cancer by human papillomavirus vaccination.

As cervical cancer is causally associated with 14 high-risk types of human papillomavirus (HPV), a successful HPV vaccine will have a major impact on this disease. Although some persistent HPV infections progress to cervical cancer, host immunity is generally able to clear most HPV infections. Both cell-mediated and antibody responses have been implicated in influencing the susceptibility, persistence or clearance of genital HPV infection. There have been two clinical trials that show that vaccines based on virus-like particles (VLPs) made from the major capsid protein, L1, are able to type specifically protect against cervical intra-epithelial neoplasia and infection. However, there is no evidence that even a mixed VLP vaccine will protect against types not included in the vaccine, and a major challenge that remains is how to engineer protection across a broader spectrum of viruses. Strategies for production of HPV vaccines using different vaccine vectors and different production systems are also reviewed.

Nicotine impairs reflex renal nerve and respiratory activity in deoxycorticosterone acetate-salt rats.

Smoking exacerbates the increase in arterial pressure in hypertension. The effect of nicotine on the baroreceptor-mediated reflex responses of renal nerve activity (RNA), heart rate, and respiratory activity (minute diaphragmatic activity [MDA]) after bolus injections of phenylephrine was compared in deoxycorticosterone acetate (DOCA)-salt sensitive and normotensive rats. Osmotic minipumps that dispensed either nicotine (2.4 mg/kg/day) or saline were implanted in DOCA and normotensive rats for 18 days. Anesthetized DOCA-nicotine, DOCA-saline, control-nicotine, and control-saline rats had mean arterial pressures (MAP) of 117 +/- 3, 110 +/- 9, 90 +/- 3, and 89 +/- 5 mm Hg, respectively. Nicotine decreased the sensitivity (p less than 0.05) of baroreceptor reflex control of RNA (% delta RNA/delta MAP) in the DOCA-nicotine rats (-0.92 +/- 0.08) compared with the DOCA-saline (-1.44 +/- 0.16), control-nicotine (-1.45 +/- 0.08), or control-saline (-1.45 +/- 0.21) rats. The reflex decrease in respiratory activity (% delta MDA/delta MAP x 100) was impaired (p less than 0.01) in both control-nicotine (-24.5 +/- 3.3) and DOCA-nicotine (-18.2 +/- 4.6) rats compared with control-saline (-59.2 +/- 9.1) and DOCA-saline (-52.5 +/- 9.9) rats. The reflex decrease in heart rate (absolute delta HR/delta MAP) in both DOCA-nicotine (1.56 +/- 0.17) and control-nicotine (1.54 +/- 0.24) rats was augmented compared with DOCA-saline and control-saline rats (0.91 +/- 0.12 and 0.97 +/- 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of chloride for deoxycorticosterone acetate-salt hypertension in the rat.

Selective dietary sodium loading (without chloride) fails to produce hypertension in the Dahl salt-sensitive rat. This study attempted to evaluate the effect of selective sodium loading on blood pressure in another NaCl-dependent model of hypertension--deoxycorticosterone acetate (DOCA)-salt hypertension. Three groups of uninephrectomized rats were studied for 32 days on one of the following regimens: (1) high NaCl diet plus DOCA, (2) high dietary sodium intake without chloride plus DOCA, and (3) high NaCl diet without DOCA. Both indirect and direct arterial pressure were higher (p less than 0.01) in the DOCA-NaCl group than in the other two groups. In the two DOCA-treated groups, net sodium and potassium balance and total carcass sodium and potassium content did not differ. In the DOCA-NaCl group, higher blood pressures were associated with a more positive chloride balance and total carcass chloride content (p less than 0.01), an expanded extracellular fluid volume (p less than 0.05), and increased renal vascular resistance (p less than 0.01). Higher renal vascular resistance in DOCA-NaCl animals suggests that chloride contributes to NaCl-induced vasoconstriction.

Effects of induced total-body hyperthermia on phosphorus metabolism in humans.

The effects of total-body hyperthermia on phosphorus homeostasis are controversial. To evaluate the problem, 10 clearance studies were performed in seven patients undergoing total-body hyperthermia as an adjunct to the treatment of solid malignant tumors. Total-body hyperthermia was associated with significant reduction in plasma phosphorus concentration from a baseline value of 3.51 +/- 0.18 to 0.6 +/- 0.1 mg/dl (p less than 0.001), returning to baseline following cessation of total-body hyperthermia. The clearance of phosphorus increased from 15.2 +/- 2.5 to 26.1 +/- 3.1 ml per minute (p less than 0.01), and the fractional excretion of phosphorus increased from 11.37 +/- 2.2 to 47.68 +/- 9.7 percent (p less than 0.01). The reduction in plasma phosphorus during total-body hyperthermia was also associated with a significant reduction in the renal threshold phosphorus concentration from 3.17 +/- 0.16 to 0.38 +/- 0.08 (p less than 0.001). The changes in phosphorus homeostasis during total-body hyperthermia were independent of changes in circulating parathyroid hormone level, urinary cyclic AMP excretion, and arterial carbon dioxide tension.

Neutrophils and renal failure.

In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils' ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This review summarizes the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. Nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase is a membrane-associated enzyme that generates a family of reactive oxygen intermediates (ROI). There is increasing evidence that ROIs are implicated in glomerular pathophysiology: ROIs contribute to the development of proteinuria, alter glomerular filtration rate, and induce morphological changes in glomerular cells. Specific neutrophil granules contain microbicidal peptides, proteins, and proteolytic enzymes, which mediate the dissolution of extracellular matrix, harm cell structures or cell function, and induce acute and potentially irreparable damage. Although both ROI and neutrophil-derived proteases alone have the potential for tissue destruction, it is their synergism that circumvents the intrinsic barriers designed to protect the host. Even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of neutrophil-derived myeloperoxidase (MPO) and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage if not properly controlled. In addition, neutrophil-derived phospholipase products such as leukotrienes and platelet-activating factor contribute to vascular changes in acute inflammation and amplify tissue damage. Increasing evidence suggests that mesangial cells and neutrophils release chemotactic substances (eg, interleukin 8), which further promote neutrophil migration to the kidney, activate neutrophils, and increase glomerular injury. Also, the expression of adhesion molecules (eg, intercellular adhesion molecule 1 on kidney-specific cells and beta-2-integrins on leukocytes) has been correlated with the degree of injury in various forms of glomerulonephritis or after ischemia and reperfusion. Together, these results suggest that neutrophils and adhesion molecules play an important role in mediating tissue injury with subsequent renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase susceptibility to infection and sepsis.

The renin-angiotensin-aldosterone system and hypertension in primary hyperparathyroidism.

To evaluate the role of the renin-angiotensin-aldosterone system in the hypertension associated with primary hyperparathyroidism, we measured plasma renin activity and aldosterone concentration before and after maneuvers to suppress and stimulate this system in 11 hypertensive patients with primary hyperparathyroidism. We also measured plasma or urinary norepinephrine concentration to examine the role of catecholamines in the hypertension. The results were compared with an age- and race-matched control population. While the mean plasma aldosterone concentrations were normal, the mean plasma renin activity in response to furosemide stimulation was subnormal in subjects with hyperparathyroidism. Plasma or urinary norepinephrine concentrations were within the normal range. Thus a specific abnormality of the renin-angiotensin-aldosterone system or catecholamines could not be identified in these hypertensives with primary hyperparathyroidism.

Effect of leukotrienes of renal water excretion.

To investigate the renal actions of leukotrienes (LT), we infused arachidonic acid into the renal artery of anesthetized dogs during systemic cyclooxygenase inhibition (with ibuprofen) alone or in combination with lipoxygenase inhibition or LTD4/LTE4 receptor antagonism. Renal arachidonic acid infusion following ibuprofen alone decreased urine osmolality (945 +/- 143 to 698 +/- 144 mosm/kg; p < 0.01) and increased urine flow rate (0.34 +/- 0.11 to 0.56 +/- 0.16; p < 0.05) without altering renal blood flow, glomerular filtration rate or sodium excretion. In separate groups, prior inhibition of lipoxygenase (propylgallate) or blockade of LTD4/LTE4 receptors (LY171883) prevented the changes in urine osmolality and urine flow rate. Intrarenal oleic acid infusion following ibuprofen had no effect on renal function. Analysis of the renal papillae at the end of the experiment indicated that interstitial osmolality and sodium, potassium and urea contents were the same in all groups, ruling out a decrease in papillary interstitial osmolality as the cause of the decrease in urine osmolality in the arachidonic acid-infused group. Our experiments suggest that renal LT can decrease urine osmolality and increase urine flow rate and may play a role in renal water excretion.

Ring scotomata in fundus flavimaculatus.

Ring scotomata were associated with fundus flavimaculatus in six patients. The demonstration of ring scotomata in patients with fundus flavimaculatus helps to explain persistent visual complaints that may exist in the presence of normal central visual acuity. In many instances, ring scotomata cannot be predicted on the basis of the ophthalmoscopic findings. The presence of ring scotomata appears to be an ominous finding, even when associated with normal central visual acuity, for in three of our patients it preceded loss of central vision by 1 1/2 to four years.

Endogenous norepinephrine regulates blood flow to the intact rat tibia.

The goal of our study was to determine if endogenous norepinephrine (NE) has a role in the regulation of basal blood flow to intact bone. The experimental plan was to measure bone blood flow before and after pharmacological blockade of alpha-adrenergic receptors. A significant increase in blood flow after receptor blockade would suggest that endogenous norepinephrine exerts a tonic constrictor effect on the vessels supplying blood to the bone. Mature, male rats were anesthetized with Inactin. Arterial blood pressure and left tibia blood flow (laser Doppler flowmetry) were measured. A cannula was inserted into the right iliac artery and advanced to the aortic bifurcation to deliver drugs into the left hindlimb circulation, including the left tibia vasculature. Bolus injection of norepinephrine caused a dose-dependent decrease in bone blood flow (30-40%). Blockade of alpha-adrenergic receptors with phentolamine or phenoxybenzamine attenuated by more than 50% the norepinephrine-induced decrease in bone blood flow. In separate rats that had not received exogenous norepinephrine, injection of phentolamine alone decreased bone vascular resistance by 34+/-3%. Similarly, phenoxybenzamine decreased resistance by 25+/-4%. These results are consistent with the conclusion that alpha-adrenergic receptors mediate a significant constriction of blood vessels which participate in the partial control of basal blood flow to the intact rat tibia.

Mechanisms mediating canine renal vasoconstriction induced by nicotine infusion.

We investigated the respective contributions of the renin-angiotensin and alpha-adrenergic systems to nicotine-induced, canine, renal vasoconstriction by using saralasin (4 micrograms/kg/min) and phentolamine (25 micrograms/kg/min) blockade respectively. Nicotine infusion (0.024 mg/kg/min) increased mean arterial blood pressure (MABP) (114 +/- 3.0 to 219 +/- 8.0 mmHg) and decreased total renal blood flow (TRBF) (3.12 +/- 0.34 to 1.60 +/- 0.37 ml/min/g). Nicotine infusion produced a significantly lesser blood flow in outer cortex (OC), inner cortex (IC), and outer medulla (OM) compared to control dogs. The intrarenal-artery infusion of saralasin or phentolamine had no effect on the nicotine-induced MABP changes. Phentolamine infusion prior to nicotine resulted in a significantly greater TRBF (P less than 0.01), OC (p less than 0.001), IC (p less than 0.001) and OM (p less than 0.01) flow than in the group that received nicotine only. Saralasin pretreatment prior to nicotine resulted only in a significantly (p less than 0.01) greater OC flow than nicotine only. Our data suggest that while angiotensin II mediates a portion of the action of nicotine on the OC renal vasculature, the alpha adrenergic system predominates as the mediator of nicotine-induced renal vasoconstriction in the first 7 minutes of nicotine infusion.

Altered expression and activity of G-proteins, mitogen activated protein kinases, and tyrosine kinases in aging kidney cortex.

BACKGROUND: Renal function declines with age and this may be related to changes in the expression or activity of various signal transduction proteins in the kidney. METHODS: The present study compared the expression and activity of G alpha i(1-3) and G alpha s phosphorylation of mitogen activated protein kinases (MAP-K) (44 and 42 kd) and the activity of tyrosine kinase in renal cortical homogenates of young (4-month-old) and aging (14-month-old) rats. RESULTS: The GTP/(GTP + GDP) binding ratio of G alpha s was significantly decreased in the kidney cortex of aging rats compared to young rats, while the GTP/(GTP + GDP) binding ratio of G alpha i(1-3) increased significantly in kidney cortex of aging rats. Tyrosine kinase activity and phosphorylation of MAP-K (44 and 42 kd) were also reduced in the kidney cortex of aging rats compared to young rats. CONCLUSIONS: These results suggest that diminished phosphorylation of MAP-K and tyrosine kinase activity as well as changes in the binding of GTP/(GTP + GDP) to G alpha i(1-3) and G alpha s may contribute to the age-related decline in renal tubular and vascular function seen in aging animals.

Acute recognition and management of congestive heart failure.

The acute recognition and management of CHF is challenging. A basic understanding of the determinants of cardiac performance and myocardial O2 consumption along with the pathophysiology of CHF is essential knowledge for the physician undertaking to treat this serious disorder. The basic value of the patient history and physical examination along with assessment of noninvasive tests remains unquestioned, but in addition much relevant and sophisticated information can be gained by invasive hemodynamic monitoring. The cardiopulmonary profile generated by such monitoring allows the physician to use specific hemodynamic and circulatory data for the purpose of manipulating these variables favorably for the heart and circulation. A wide array of therapeutic options is currently available, but, in general, respiratory support and pharmacotherapy are the mainstays of treatment. The traditional agents like digitalis and diuretics have assumed a lesser role during the last decade because of the availability of potent new vasodilator and inotropic agents. In addition, certain mechanical, procedural, and surgical options can be used if circumstances are urgent. In the final analysis, physicians who manage these patients must possess strong cognitive skills but also the clinical reflexes to carry them out: for every hemodynamic and circulatory action, they must be prepared to counter quickly and decisively with a clinical reaction which utilizes these principles to optimize cardiac function. It is hoped that the strategies presented in this article will allow them to perform in such a manner.

Effect of indomethacin on mesenteric circulation in mongrel dogs.

Necrotizing enterocolitis has been attributed to the use of indomethacin (INDO) for medical closure of patent ductus arteriosus. To study the effect of INDO on cardiac output and mesenteric circulation, INDO was given by rectum (0.25 mg/kg, 0.5 mg/kg, 1.25 mg/kg--3 dogs in each group) and the control group received none. The cardiac output and organ blood flow were measured before and 1 hr after INDO with radioactive microspheres using 4 isotopes (Cr53, Ni95, Co57, Sn113). The blood flow to different parts of the GI tract was measured as percent of cardiac output using a gamma counter. Paired t test was used to calculate percent reduction in organ blood flow. During the experiment, there was no reduction in cardiac output in the entire group. Anesthesia had no effect on the control group. In the three INDO treated groups, percent reduction of mucosal blood flow of the stomach (63%, 32%, 68%, p less than 0.01), mid ileum (19%, 59%, 57%, p less than 0.05) and terminal ileum (57%, 35%, 54%, p less than 0.015) was significant. A strong trend in reduction of organ blood flow was noted in other regions. There was no significant change due to different dosages of INDO. The area of ischemia in this dog model corresponds to clinical pathology noted in necrotizing enterocolitis.